6,7,8-trialkyl-quinazolines having a hydroxyalkyl bearing 4-amino function

ABSTRACT

DISCLOSED ARE COMPOUNDS OF THE CLASS OF QUINAZOLINES SUBSTITUTED IN THE BENZENE RING PORTION OF THE QUINAZOLINE BY TRIALKOXY AND FURTHER SUBSTITUTED AT THE 4-POSITION BY AN AMINO FUNCTION BEARING A HYDROXYALKYL MOIETY, E.G., 4-(5-HYDROXYPENTYL)AMINO - 6,7,8-TRIMETHOXYQUINAZOLINE. THE COMPOUNDS HAVE PHARMACOLOGICAL ACTIVITY IN ANIMALS AND ARE USEFUL, FOR EXAMPLE, AS HYPOTENSIVE, CORONARY DILATORS AND ANTIANGINAL AGENTS. THE COMPOUNDS ARE PREPARED FROM THE CORRESPONDING 4-HALOQUINAZOLINES BY KNOWN PROCEDURES AND ARE ALSO USEFUL IN PREPARATION OF THE CORRESPONDING HYDROXY NITRATES WHICH ARE USEFUL, E.G., AS ANTIANGIBAL AGENTS

United States Patent 1 3,833,587 6,7,8-TRIALKYL QUINAZOLINES HAVING AHYDROXYALKYL BEARING 4 AMINO FUNCTION Lloyd P. Gabel, Morris Plains, andWilliam R. J. Simp. .son, Hanover,, N.J., assignors to Sandoz-Wander,Inc., Hanover, NJ, NoDrawing. Application Nov. 13, 1970, Ser. No.89,472,

now Patent No. 3,637,700, which is a continuation-inpart of abandonedapplication Ser. No. 870,439, Dec. 5, 1 969. Divided and thisapplication Sept. 15, 1971, Ser'.No.'180,762 I v Int; Cl.'C07d 51/48U.S.'Cl. 260256.4 Q 1 5 Claims ABSTRACT OF THE DISCLOSURE Disclosed arecompounds'of the class of quinazolines substituted in the benzene ringportion of the quinazoline by trialkoxy and further substituted at the4-position by an amino function'bearing a hydroxyalkyl moiety, e.g.,4-'(5-hydroxypentyl) amino 6,7,8-trimethoxyquinazoline. The compoundshave pharmacological activity in animals and are usefnlyfor example, ashypotensive, coronary dilators and antianginal agents. The compounds areprepared from the corresponding 4-haloquinazolines by known vproceduresand are also useful in preparation of the corresponding hydroxy nitrateswhich are useful, e.g., as antianginal agents.

This application is a division of Ser. No. 89,472, filed Nov. 13, 1970,now U.S. Letters Patent No. 3,637,700, whichin turn is acontinuation-in-part of Ser. No. 870,439, filed Dec.,S,, 1969, nowabandoned.

' This invention relates to quinazoline derivatives, and moreparticularly to quinazolines which are substituted in the benzene ringportion thereof by three alkoxy groups and also substituted at the4-position by an amino function bearing a hydroxyalkyl nitrate moiety.The invention also relates to pharmaceutical methods and compositionsutilizing said compounds. The invention fur- 'ther relates tocorresponding hydroxyalkyl substituted quinazolines useful asintermediates in preparation of said nitrates.

The compounds of the invention may be represented by the structuralformula I:

,Y 1 Y W Y wherein R' is from the group of R, is from the'group of I U(f) loweralkyl of 1 to 4 carbon atoms, 1 ,is hydrogen, (CH CH or (CH ONOprovided that "one R' (and only one) is other than hy- Qdrogen, that thesum'of in and m does not'exceed 6 and 1 "thatth'e surnof'n and does notexceed 7, or

3,833,587 Patented Sept. 3, 1974 ICC a pharmaceutically acceptablenon-toxic acid addition salt thereof.

A preferred method for preparation of the compounds of formula Iinvolves in a Step A reaction the nitration of the corresponding hydroxycompound of formula 11:

Y W Y N wherein Y, Y and Y" are as defined and R and R are thenon-nitrate bearing hydroxyalkyl substituents corresponding to R and Rrespectively, i.e.:

R is from the group of:

R is from the group of:

(d) CH (--CH ),,OH when R is (a) as above defined, (e) hydrogen, and (f)lower alkyl of 1 to 4 carbon atoms, R is hydrogen, -(CH CH or -(CH OH,provided that one R,, is other than hydrogen, that the sum of n and 1mdoes not exceed 6 and that the sum of n and y does not exceed 7, or Rand R together with the 4-amino nitrogen attached to the quinazolinering form -N N-CHK-CHa) -OH, and

n, m, y and z are as defined.

The preparation of compounds I by Step A involves a nitration reactionwhich may be carried out in a manner known per se for nitratinghydroxyalkyl groups. A pre:

The solvent medium for the reactionis preferably pro-1 vided byemploying a lower aliphatic carboxylic acid, e. g.

acetic acid, although other ,Well known organic solvents may be employedor the reaction may be carried out employing an excess of the carboxylicacid anhydride. The product compound I may be isolated from the reactionmixture of Step. A by working up by established procedures.

A preferred method for preparation of compounds II involves a Step Breaction of a 4-haloquinazoline of formula III wherein Y, Y and Y" areas defined and X is halo from the group of chloro or bromo, preferablychloro, with a compound of formula IV:

wherein R and R are as defined.

The reaction of Step B is of known type and may be carried out in aconventional manner by subjecting a compound III to reaction with thecompound IV in an organic solvent at elevated temperatures which may besuitably in the range of 30 C. to 150 C., preferably 50 C. to 100 C. Thereaction is carried out in an inert organic solvent which may be any ofseveral of the well-known conventional solvents, preferably an aromaticsolvent such as benzene. Another preferred solvent is isopropanol.Alternately, the reaction may be carried out in the inert liquid mediumprovided by employing an excess of compound IV. An acid binding agentsuch as sodium carbonate may be also employed to advantage in thereaction, if desired. The reaction product compound II may be isolatedfrom the reaction mixture of Step B by established procedures.

The compounds of formula IV are either known or may be prepared fromknown materials by established procedures. The compounds of Formula IIIare preferably prepared by the procedure described and illustratedhereinafter in Steps A-C, inclusive, of Example 1. The compounds offormula III are novel compounds as are also the correspondingtrialkoxy-quinazolin-4(3H)-ones which are preferably prepared by theprocedure described and illustrated in Steps A and B of Example 1. The2-nitro 3,4,5-trialkoxy methyl benzoates used in preparing thequinazolin-4(3H) -ones are either known or may be prepared from knownmaterials by established procedures.

Also within the scope of the novel compounds of the invention arepharmaceutically acceptable salts not materially affecting thepharmacological effect of the compounds of formula I and formula II.Such salts include the acid addtion salts, e.g., the methane sulfonate,hydronitrate, hydrosulfate, fumarate, hydrochloride and maleate. It isconvenient to prepare the compounds of formula I as a hydronitrateaddition salt. Such salts may be then readily converted to the freebases by conventional procedures. In preparing the free bases from theacid addition salt it is also convenient to employ a buifer system,e.g., a system comprising a 1:1 molar mixture of acetic acid and sodiumacetate, followed by Working up by conventional procedures. The freebases may be readily converted into the hydronitrate and other acidaddition salts by established procedures.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts are useful because they possess pharmacological activityin animals. In particular, the compounds are useful as hypotensiveagents, as indicated by a lowering of blood pressure on intravenousadministration to the anesthetized dog. The compounds of the inventionare also useful as coronary dilators in the treatment of cardiacinsufliciencies, as indicated on intravenous administration to theanesthetized dog and measurement of blood flow through the anteriordescending branch of the left coronary artery. The compounds are furtheruseful as antianginal agents as indicated by effecting coronary dilationin the above-indicated test and by showing a 4S 1 reduction of oxygenconsumption and increase in coronary blood flow in the known testinvolving a determination of myocardial oxygen consumption in theanesthetized dog.

For the above uses, the compounds may be combined with apharmaceutically acceptable carrier, and such other conventionaladjuvants as may be necessary, and administered orally in such forms astablets, capsules, elixirs, suspensions and the like or parenterally inthe form of an injectable solution or suspension. For the above'mentioned uses, the dosage administered'will, of course, var'ydepend ingupon the compounds used, the therapy desired and the mode ofadministration. However, as hypotensivejnd, coronary dilator agents,satisfactory resultsa're obtained when administered at a daily dosage offrom'fabout 0.1 milligrams to about 50 milligrams per kilogram of bodyweight, preferably given in divided doses 2 to .4-times a day, or insustained release form; For most mammals the administration of fromabout 6 milligrams to a bout 500 milligrams of the compound per dayprovides satisfactory results and dosage forms suitable for internaladministra tion comprise from about 1.5 milligrams to about 250milligrarns of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

As antianginal agents satisfactory results may be obtained whenadministered at a daily dosageof from 0.002 to 20 milligrams perkilogram of bodyweight, given as required or in divided doses or insustained release form. For most mammals a dosage of from 0.1 to 60milligrams, pro re nata, provides satisfactory results. The compoundsmay also be used prophylactically in mammalsto prevent or minimizeangina attacks at a daily dosageof 0.1 to 60 milligrams, or in divideddoses of from 0.025 to 30 milligrams. i

The compounds of Examples 1, 2b, 2d and 2z are also useful asantiarrhythmic agents, as indicated by polygraph recordings onintravenous administration to the anesthetized dog given Ouabain untilthe appearance of constantly-occurring ventricular ectopic beats andthen the test compound every two minutes until the arrhythmia reverts tosinus rhythm. For this use satisfactory results, in general, areobtained when administered at a daily dosage of from 0.05 to 50milligrams per kiolgram of animal body weight. For most mammals theadministration of from 3 to milligrams of the compound per day pro videssatisfactory results and divided dosage forms suitable for internaladministration comprise fromabout 0.75 to 50 milligrams in admixturewith a solid or liquid pharmaceutical carrier or diluent.

For above usages, oral administration with carriers may take place insuch conventional forms as tablets, dispersible powders, granules,capsules, syrups and elixirs. Such compositions may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,i.e., inert diluents such as calcium carbonate, sodium carbonate,lactose and talc, granulating and disintegrating agents, e.g., starchand alginic acid, binding agents, e.g., starch, gelatin and acacia, andlubricating agents, e.g., magnesium stearate, stearic acid and talc. Thetablets may be uncoated or coated by known techniques to delaydisintegration and adsorption in the gastro-intestinal tract and therebyprovide a sustained action over a longer period. Similarly, suspensions,syrups and elixirs may contain the active ingredient in admixture withany of the conventional excipients utilized for the preparation of suchcompositions, "e.g., suspending agents (methylcellulose, tragacanth andsodium 'alginate), wetting agents (lecithin, polyoxyethylene'istearate"and polyoxyethylene sorbitanmonooleate) and preservatives(ethyl-p-hydroxybenzoate). Qapsules may contain, the

Ingredient: Weight (mg) Compound of the formula I, e.g., a compound ofExamples I, 2b, 2d, 2x or 2z, hereinafter 11.55

Lactose (spray-dried) 151.3 Collodial Silica (Cab-O-Sil) 5.45 AlginicAcid 56.7

The compounds of the formula II and their pharmaceutically acceptableacid addition salts are also useful because they possess pharmacologicalactivity in animals. In particular, the compounds are useful ashypotensive agents and as coronary dilators in the treatment of cardiacinsufficiencies as indicated by the above-indicated tests in animals forthese activities. Based on further evaluations of the compound producedin Step D of Example 1, it is also indicated that compounds of theformula H may be used as anti-anginal agents as indicated by effectingcoronary dilation in the above-indicated test and by showing a reductionof oxygen consumption and increase in coronary blood flow in theabove-referred to myocardial oxygen consumption test. Similarly, it isnoted that the product of Step D of Example 1 is also indicated asuseful as an anti-arrhythmic agent as indicated by the above-mentionedanimal test for determining such indication. For the above uses of thecompounds of formula II the dosage will vary depending upon knownfactors such as mode of administration and the particular compoundemployed. However, in general, satisfactory results are obtained at adaily dosage of from about 0.3 to about 80 milligrams per kilogram ofbody weight. For most mammals a daily dosage of from 20 to 600milligrams provides satisfactory results with divided dosage formscomprising from about 5-300 milligrams, except that in the use asanti-anginal agents a dose of from 2 to 150 milligrams may beadministered pro re nata. For prophylactic use of the compounds of theformula II in preventing or minimizing angina attacks av daily dosage offrom 2 to 150 milligrams or divided doses of from 0.5 to 75 milligramsare indicated. The compounds of the formula 11 may be administered fortheir particular uses in the conventional forms and modes aboveindicated for the administration of the compounds of formula I.

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only.

EXAMPLE 1 4- 3-Bis (Z-hydroxyethyl) aminopropyl] amino-6,7,8-trimethoxyquinazoline dinitrate dimaleate onto /N\ L -dimaleate CH3 0STEP A: Preparation of 2-amino-3,4,5-trimethoxy methyl benzoate Amixture of 39 g. of 2-nitro-3,4,5-trimethoxy methyl benzoate, 100 ml. ofacetic acid and 2.5 g. of 5% palladium on charcoal is shaken withhydrogen at temperature of 60 C. and a hydrogen pressure of 50 p.s.i.for 25 hours. The resulting mixture is filtered and concen- 6 trated invacuo. The resulting residue is partitioned between methylene chlorideand an excess of sodium carbonate solution. The methylene chloridesolution is dried, concentrated in vacuo and the resulting oil distilled(105 C. 5X10 mm.) to obtain an oil of 2-amino-3,4,5- trimethoxy methylbenzoate.

STEP B: Preparation of 6,7 ,8-trimethoxy-quinazolin-4 (3H)-one Asolution of 24.2 g. of 2-amino-3,4,5-trimethoxy methyl benzoate in ml.of 99% formamide is refluxed for 1% hours. The reaction mixture is thencooled, 200 ml. of ice water is added, and the solid material isseparated by filtering, washed with water and dried to obtain6,7,8-trimethoxy-quinazolin-4(3H)-one, m.p. 220-222 c STEP C:Preparation of 4-chloro-6,7,8,-trimethoxyquinazoline STEP D: Preparationof 4-[3-bis (Z-hydroxyethyDaminopropyl]amino-6,7,S-trimethoxy-quinazoline A mixture of 6 g. of4-chloro-6,7,8-trimethoxyquinazoline, 4.2 g. ofbis(2-hydroxyethyl)aminopropylamine and 3.5 g. of sodium carbonate isheated in 50 m1. of refluxing isopropanol for 35 minutes. The reactionmixture is then filtered, solvent removed in vacuo and the crystallineresidue recrystallized from ethyl acetate to obtain 4- [3-bis(2-hydroxyethyl) aminopropyl] amino-6,7,

8-trimethoxyquinazoline, m.p. l42.5144 C.

STEP E: Preparation of 4-[3-bis(2-hydroxyethyl) aminopropyl] amino 6,7,8trimethoxy-quinazoline dinitrate dimaleate A solution of 6.42 g. of 4 [3bis(2 hydroxyethyl) aminopropyl] amino 6,7,8-trirnethoxy-quinazoline in30 ml. of glacial acetic acid is added over a period of 6 minutesdropwise to a stirred cooled (310 C.) mixture of 14.2 ml. of aceticanhydride and 4.73 ml. of nitric acid. Stirring is continued for 5minutes after addition and the resulting mixture added to 300 ml. of abutter system comprising a 1:1 molar mixture of acetic acid solution andsodium acetate solution. The resulting mixture is extracted three timeseach with 200 ml. of ethyl acetate, washed with excess of sodiumcarbonate solution at temperature of 5 0., dried and concentrated invacuo to obtain a solid which is treated with a solution of 3.08 g. ofmaleic acid in 25 ml. of ethanol. The resulting mixture is concentratedin vacuo to obtain a solid material which is filtered off, washed withcold (0 C.) ethanol, dried and recrystallized from methanol to obtain4-[3-bis(2-hydroxyethyl)aminopropyl]amino 6,7,8-trimethoxy-quinazolinedinitrate dimaleate, m.p. 107 C. (decomp.). Following the same procedurebut employing hydrogen chloride in place of the maleic acid, there isreadily prepared the dihydrochloride salt, m.p. 146 C. (decomp.).

EXAMPLE 2 Following the procedures of Example 1 there is obtained (a)4-(G-hydroxyhexyl)amino-6,7,8-trimethoxyquinazoline, m.p. 143-144 C.(Crystallization from ethyl acetate).

(b) 4-(6-hydroxyhexyl) amino-6,7,8-trimethoxyquinazoline nitratemaleate, m.p. 106107 C. (Crystallization from ethanol/diethyl ether).

(c) 4-(5-hydroxypentyl)amino-6,7,8-trimethoxyquinazoline', m.p.143-144"C. (Crystallization from ethyl acetate).

(d) 4-(5-hydroxypentyl)amino-6,7,8-trimethoxyquinazoline nitratemaleate, m.p. 110 C. (decomp.).

(Crystallization on addition of diethyl' ether to oily product).

(e) 4-(4-hydroxybutyl)amino-6,7,8-trimethoxyquinazoline, m.p. 174-174.5C. (Crystallization from ethyl acetate).

(f) 4-(4-hydroxybutyl)amino-6,7,8-trimethoxyquinazoline nitrate maleate,m.p. 114115 C. (Crystallization from methanol/diethyl ether andrecrystallized from ethanol).

(g) 4-[4-(2-hydroxyethyl) l-piperazino] -6,7,8-triethoxyquinazoline,m.p. 100-102 C.

(h) 4- [4- 2-hydroxyethyl) -1-piperazino] 6,7 ,S-triethoxyquinazolinenitrate dihydrochloride, m.p. 170 C. (decomp.).

(i) 4-(5-hydroxypentyl)amino-6,7,8-triethoxyquinazoline, m.p. 109-110.5C.

(j) 4- S-hydroxypentyl) amino-6,7,8-triethoxyquinazoline nitratehydronitrate, m.p. 78-79 C.

(k) 4- [3-bis 2-hydroxyethyl) aminopropyl] amino-6,7,8-

triethoxyquinazoline, m.p. 9394 C.

(l) 4- [3-bis (2-hydroxyethyl) aminopropyl] amino-6,7,8-

triethoxyquinazoline dinitrate dihydrochloride,

m.p. 130 C. (decomp.).

(m) 4- 3-bis B-hydroxypropyl) aminopropyl] amino-6,7,8-trirnethoxyquinazoline, m.p. 117-118 C.

(n) 4- [3-bis 3-hydroxypropyl) aminopropyl] amino-6,7,S-trimethoxyquinazoline dinitrate, m.p. 120-12l C. (decomp.).

(o) 4-[4-bis(2-hydroxyethyl)aminobutyl]amino-6,7,8-

trimethoxyquinazoline, m.p. 159-160 C.

(p) 4- [4-bis (2-hydroxyethyl aminobutyl] amino-6,7,8-trimethoxyquinazoline dinitrate dihydrochloride, hydroscopic and nomelting point obtained.

(q) 4- (4-hydroxymethyl-S-hydroxypentyl) amino-6,7,8-

trimethoxyquinazoline, m.p. 155160 C.

(r) 4-(4-hydroxymethyl-5-hydroxypentyl)amino-6,7,8-trimethoxyquinazoline dim'trate hydronitrate, m.p. 114.5-115" C.

(s) 4-N-methyl-N-[3-bis(2-hydroxyethyl)aminopropyl]amino-6,7,8-trimethoxyquinazoline, m.p. 89-91 C. (t) 4-N-methy1-N- 3-bis(2-hydroxyethyl) aminopropyl] amino-6,7,8-trimethoxyquinazolinedinitrate fumarate, m.p. 79-81 C.

(u) 4-di(2-hydroxyethyl)amino-6,7,8-trimethoxyquinazo1ine,'m.p. 113 C. i

(v) 4-di(2-hydro'xyethyl)amino-6,7,8-trimethoxyquinaz'oline dinitratehydronit'rate, m.p. 121-122" C.

(decomp.). i

(w) 4-(2,3-dihydroxypropyl)amino-6,7.84rimethoxyq'uina'zoline, m.p. -186C. l

(x) 4-(2-,-'3-dihydroxypropyl)amino 6,7,8-trimethoxyquinazolinedinitrate maleate, m.p. 139-140 C.

(y) 4- 2-bis 2-hydroxyethyl] aminoethyl] amino-6,7, 8-trimethoxyquinazoline, m.p. 153-154 C.

(z) 4- [2-bis 2-hydroxyethyl) aminoethyl] amino-6,7,8-trimethoxyquinazoline dinitrate dihydrochloride, m.p. 136 C. (decomp.)

What is claimed is:

1. A compound of the formula:

in which each of Y, Y and Y is alkoxy of 1 to 3 carbon atoms, R ishydrogen or alkyl of 1 to 4 carbon atoms, 2 is 1 to 4 and y is 1 to 4,or a pharmaceutically acceptable non-toxic acid addition salt thereof.

2. The compound of claim 1 in which 2 is 2 and y is 1, Y, Y' and Y" aremethoxy and R is hydrogen.

3. The compound of claim 1 in which z is 1 and y is 1, Y, Y and Y aremethoxy and R is hydrogen.

4. The compound 4 (2,3 dihydroxypropyDamino 6,7,8-trimethoxyquinazoline,or a pharmaceutically acceptable non-toxic acid addition salt thereof.

5. The compound 4-[4 (2 hydroxyethyl) 1piperazino]-6,7,S-triethoxyquinazoline, or a pharmaceutically acceptablenon-toxic acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,517,005 6/1970 Cronin et a1.260-2564 RAYMOND V. RUSH, Primary Examiner

